An estimate 6,800 new HIV-1 infections daily dramatically underscores the desperate need for the development of an HIV-1 vaccine. Despite significant advances in our understanding of both the humoral and cellular immune response in HIV-1 infection, the correlates of protection have still not been defined. The recent failure of the Merck vaccine trial and the unexpected modest success of the RV144 HIV vaccine trial using ALVAC-HIV (vCP1521) in a prime boost combination with AIDSVAX B/E, have challenged our notion of what constitutes a protective vaccine. Strikingly, the vaccine induced not only strong antibody responses, but also a robust HIV-1-specific CD4+ T cell response. Approaches to induce HIV-1-specific CD4+ T cell responses have been met with skepticism thus far as these attempts may expand the pool of HIV-1 specific CD4+ T cells targets. However, compelling studies in the lymphochoriomeningitis virus (LCMV) mouse model suggest that virus-specific Interleukin-21 (IL21) secreting CD4+ T cell responses are a critical key factor to establish effective and long-lived virus-specific immunity. Mice lacking IL21 or IL21 receptor (IL21R) were more susceptible to chronic LCMV infection. IL21+CD4+ T cell responses have been shown to enhance cytotoxicity of virus-specific CD8+ T cells and direct antibody class switching and activation of B cells. Thus, IL21+CD4+ T cell responses play a central role in the coordination of virus-specific immunity. Surprisingly little is known about the role of IL21+ CD4+ T cells in human viral infections. Our preliminary data suggest that robust HIV-1- specific IL21+CD4+ T cell responses exist in HIV-1 elite controllers with a preferential targeting of epitopes within the Gag protein. In contrast, in subjects with chronic-progressive HIV-1 infection virtually no IL21+CD4+ T cell responses are detectable. Moreover, we have evidence that IL21 signals can transform non-controlling CD8+ T cell responses into CD8+ T cell responses with strong inhibitory activity. Thus, our preliminary data suggest that IL21+CD4+ T cell responses might be a critical factor for the generation of an effective CD8+ T cell or B cell based vaccine. Specifically we propose to: 1) Determine the presence and specificity of HIV-1-specific IL21+CD4+ T cells as well as their role in the control of viral replication. 2) Determine whether early antiretroviral treatment in primary HIV-1 infection preserves these particular responses. 3.) Assess how HIV-1-specific IL21+CD4+ T responses modulate HIV-1-specific CD8+ T cells and enhance their capacity to inhibit viral replication. 4.) Investigate whether therapeutic CD4-targeted vaccination can induce such responses and finally 5.) assess how IL21+CD4+ T cells modulate HIV-1-specific B cell functions. The underlying hypotheses of this proposal are that HIV-1-specific IL21+ CD4+ T cells have a key function in the control of viral replication by modulating HIV-1-specific B cell function and increasing the inhibitory activity of HIV-1-specific CD8+ T cells. The induction and propagation of these responses in a prophylactic or therapeutic vaccine will be essential for long-lived effective virus-specific immunity. PUBLIC HEALTH RELEVANCE: With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX;"Thai trial") drastically demonstrate our poor understanding how to develop an effective vaccine. Strikingly, the used vaccine not only induced antibodies, but also a robust HIV-1-specific CD4+ T cell response. Recent data from the mouse model suggest that virus-specific Interleukin-21 (IL21)-secreting CD4+ T cell responses are critical to support virus-specific CD8+ T cell and B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific IL21+CD4+ T cell responses in the control of HIV-1 infection to determine whether the induction of these responses should be a key component of a prophylactic and therapeutic vaccine.